Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001242116 | SCV001415183 | pathogenic | not provided | 2024-10-14 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Gln526*) in the LZTR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LZTR1 are known to be pathogenic (PMID: 24362817, 25335493, 25480913, 25795793, 29469822, 30368668, 30442762, 30442766, 30481304, 30859559). This variant is present in population databases (rs768530578, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with LZTR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 967250). For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002402766 | SCV002710062 | pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2024-09-03 | criteria provided, single submitter | clinical testing | The p.Q526* variant (also known as c.1576C>T), located in coding exon 14 of the LZTR1 gene, results from a C to T substitution at nucleotide position 1576. This changes the amino acid from a glutamine to a stop codon within coding exon 14. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Loss-of-function variants in LZTR1 are related to an increased risk for schwannomas and autosomal recessive Noonan syndrome; however, such associations with autosomal dominant Noonan syndrome have not been observed (Piotrowski A et al. Nat Genet. 2014 Feb;46:182-7; Yamamoto GL et al. J Med Genet. 2015 Jun;52:413-21; Johnston JJ et al. Genet Med. 2018 10;20:1175-1185). Based on the supporting evidence, this variant is pathogenic for an increased risk of LZTR1-related schwannomatosis (SWN) and would be expected to cause autosomal recessive Noonan syndrome when present along with a second pathogenic or likely pathogenic variant on the other allele; however, the association of this alteration with autosomal dominant Noonan syndrome is unlikely. |
| Fulgent Genetics, |
RCV005029823 | SCV005656758 | pathogenic | Noonan syndrome 2; LZTR1-related schwannomatosis; Noonan syndrome 10 | 2024-02-26 | criteria provided, single submitter | clinical testing | |
| Clinical Genomics Laboratory, |
RCV005054351 | SCV005688750 | pathogenic | Noonan syndrome 2 | 2023-11-27 | criteria provided, single submitter | clinical testing | The LZTR1 c.1576C>T (p.Gln526Ter) variant has been reported in the literature in a single individual with schwannomatosis, but no additional information was reported (Louvrier C et al., PMID: 29409008). This variant has been reported in the ClinVar database as a germline pathogenic variant by two submitters. This variant is only observed on 5/234,626 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant causes a premature termination codon, which is predicted to lead to nonsense mediated decay. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. |